Cell Subsidiary: Combining new drug combinations to overcome cancer-resistant tumors by 50%

Cell Subsidiary: Combining new drug combinations to overcome cancer-resistant tumors by 50%

August 27, 2018 Source: Biological Exploration of: exploration bacteria

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Almost without exception, all known high-efficiency anticancer drugs will not be effective for a long time, and will develop resistance with rapid mutation of tumor cells. Recently, chemists from the University of Texas at Austin and South Korea University have found a new way to overcome drug resistance by reprogramming the oncogene-directed mitochondrial metabolism changes before drug activation, thereby increasing cancer cell apoptosis. , inhibit the regeneration of drug-resistant tumors.

Image source: University of Texas at Austin

The latest findings are published in the journal Chem "The Overcoming Drug Resistance by Targeting Cancer Bioenergetics with an Activatable Prodrug."

Co-author and Professor Jonathan Sessler of the University of Texas at Austin said, "Our joint drug candidate is more effective than the most powerful anticancer drug on the market, and the results are shocking."

A team led by South Korean University's Sessler and Jong Seung Kim developed a drug called C1 that simultaneously keeps cancerous tumors in a vulnerable state and releases powerful toxins. Two months later, the tumors of the tumor-bearing mice treated with the drug were about 75% smaller than those of the untreated mice, and the tumor volume was half that of the same drug alone.

It is understood that the C1 drug partially functions by targeting the metabolism of the tumor. In the beginning, cancer tumors were like a runner who was too fast-paced: breathing difficulties. It grows too fast and burns too much energy, making it impossible to get enough oxygen. Under normal circumstances, cells in the body need to use oxygen metabolism, but early tumors turn into anaerobic metabolism, and the efficiency is low. Like a tired runner, panting and cramping, at this early stage, the tumor's metabolism is abnormal and very fragile, so this is the time when many cancer drugs work best. However, as tumors mature and metabolism changes, tumor cells often develop resistance, which is a fatal twist for patients.

Sessler said, "When a tumor turns into a normal metabolism, it produces resistance. If we stop this transformation, then we can continue to exploit the fragility of the tumor."

Two months later, mice with human breast cancer tumors (injected with C1) were 75% smaller (pink) than untreated mice (grey gray), compared to the same drugs alone (Dox and DCA) The mouse (blue) has a small tumor half. Image source: University of Texas at Austin

The innovation in C1 in the latest study is that it links anticancer drugs to molecules that prevent tumors from breathing normally. There are two active elements in C1, the Doxorubicin (Dox) and dichloroacetic acid (DCA) subunits. Dox is a powerful cancer chemotherapy drug that has been used for decades; DCA can convert cell metabolism into anaerobic. The researchers did not invent these two elements, but they were the first to combine them into a single molecule and test it on tumor-bearing mice.

Sessler said that the key to the effectiveness of C1 is to combine the two active elements in one molecule so that when they reach the cancer cells, they are in the same position at the same time. The third element targets a subset of cancer cells called mitochondria and then releases Dox and DCA. The latter design element ensures that the two active drug elements are delivered in the most efficient place.

In this study, tumors in mice have developed resistance to the chemotherapeutic drug Dox, suggesting that the combination of experimental drugs did overcome drug resistance. Researchers have applied for patents for their C1 drugs.

Sessler is a patient patient who has been working on finding a cure for his career. “Now, cancer diagnosis is usually the death penalty,” Sessler said. "We hope to see cancer becoming a chronic disease in our lifetime."

Reference material

Keeping cancer out of breath blocks drug resistance

Original title: Cell Supplement: Tumor shrinks by 50%! Combined new drug combination to overcome cancer drug resistance

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